Pentosan polysulfate inhibits atherosclerosis in watanabe heritable hyperlipidemic rabbits; differential modulation of metalloproteinase-2 and -9

Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis

The Causal Structure of Emotions in Aristotle: Hylomorphism, Causal Interaction between Mind and Body, and Intentionality

Recently, a strong hylomorphic reading of Aristotelian emotions has been put forward, one that allegedly eliminates the problem of causal interaction between soul and body. Taking the presentation of emotions in de An. I 1 as a starting point and basic thread, but relying also on the discussion of Rh. II, I will argue that this reading only takes into account two of the four causes of emotions, and that, if all four of them are included into the picture, then a causal interaction of mind and body remains within Aristotelian emotions, independent of how strongly their hylomorphism is understood. Beyond the discussion with this recent reading, the analysis proposed of the fourfold causal structure of emotions is also intended as a hermeneutical starting point for a comprehensive analysis of particular emotions in Aristotle. Through the different causes Aristotle seems to account for many aspects of the complex phenomenon of emotion, including its physiological causes, its mental causes, and its intentional object

Umbral Calculus, Discretization, and Quantum Mechanics on a Lattice

`Umbral calculus' deals with representations of the canonical commutation relations. We present a short exposition of it and discuss how this calculus can be used to discretize continuum models and to construct representations of Lie algebras on a lattice. Related ideas appeared in recent publications and we show that the examples treated there are special cases of umbral calculus. This observation then suggests various generalizations of these examples. A special umbral representation of the canonical commutation relations given in terms of the position and momentum operator on a lattice is investigated in detail.Comment: 19 pages, Late

The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism